Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

组蛋白 H3.3 甘氨酸 34 到精氨酸/缬氨酸 (G34R/V) 突变驱动致命的神经胶质瘤并显示出精致的区域和时间特异性，表明发育环境允许其影响。在这里，我们显示 50% 的 G34R/V 肿瘤（n = 95）具有激活的PDGFRA突变，这些突变在复发时表现出很强的选择压力。尽管被认为是神经胶质瘤，但 G34R/V 肿瘤实际上出现在表达GSX2 / DLX的中间神经元祖细胞中，其中 G34R/V 突变会损害神经元分化。起源谱系可能通过连接PDGFRA和GSX2调节元件的染色质环促进PDGFRA 的共同选择，促进PDGFRA过度表达和突变。在单细胞水平上，G34R/V 肿瘤具有双重神经元/星形胶质细胞特性，缺乏少突胶质细胞程序，被GSX2/DLX介导的细胞命运规范积极抑制。G34R/V 对于肿瘤维持可能变得可有可无，而突变型PDGFRA具有强致癌性。总的来说，我们的结果为致命肿瘤开辟了新的研究途径。G34R/V 神经胶质瘤是神经元恶性肿瘤，其中中间神经元祖细胞因 G34R/V 突变而停滞在分化中，并且通过共同选择潜在的可靶向途径PDGFRA信号促进恶性胶质细胞生成。